Novel benzo(b)thiophene derivatives and processes for their preparation

ABSTRACT

The present invention relates to novel benzo(b)thiophene derivatives of the general formula:   WHEREIN Y represents a hydrogen or halogen atom; A represents a hydrogen atom or a phenyl group which may be substituted with a halogen atom or a lower alkoxy group; B represents a radical of the formula OR&#39;&#39; or NR2R3, wherein R&#39;&#39; is an alkyl radical of 1 to 5 carbons which may be substituted with hydroxy, lower alkoxy, phenyl or phenoxy groups or a cycloalkyl or phenyl group which may be substituted by lower alkoxy or halogen atoms; R2 and R3, which may be identical or different, represent, if identical, hydrogen, alkyl radicals of 1 to 5 carbon atoms which may be substituted by hydroxy, lower alkoxy, phenoxy, di-lower alkylamino, or phenyl groups; or, if R2 is hydrogen, R3 represents either a hydroxyl or an amino group which may be substituted by lower alkyl, dialkyl, alkylidene, phenyl or acyl groups or a lower alkyl group which may be substituted by hydroxy, lower alkoxy, phenoxy, dialkylamino, pyrrolidino, piperidino or morpholino groups; R3 further is a cycloalkyl or phenyl group, which may be substituted by a halogen or a lower alkoxy radical; or R2 and R3 together with the nitrogen altom to which they are attached, may form an aziridine, pyrrolidine, piperidine, morpholine or piperazine ring which may be substituted by lower alkyl, hydroxyalkyl, phenylalkyl, phenyl or acetyl groups; or A and B together with the C N group may form a 5, 6, or 7-membered heterocyclic ring. The present invention further relates to the processes for the preparation of these derivatives and to the salts of these compounds with physiologically acceptable inorganic and organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, fumaric acid, oxalic acid, citric acid, etc., and the quaternary ammonium compounds.

United States Patent [191 Stoss et al.

[ Sept. 23, 1975 NOVEL BENZO(B)THIOPHENE DERIVATIVES AND PROCESSES FOR THEIR PREPARATION [75] Inventors: Peter Johannes Stoss, Wildtal;

Manfred Franz Reinhold Ilerrmann,

Gundelfingen; Gerhard Satzinger, Denzlingen, all of Germany [73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

22 Filed: Nov. 27, 1973 21 Appl. No.: 419,305

[30] Foreign Application Priority Data Nov. 27, 1972 Germany 2258036 [52] US. Cl.. 260/3305; 260/247.l P; 260/268 BC; 260/293.57; 260/294.8 C; 260/294.8 D;

[51] Int. Cl. C07D 333/52 [58] Field of Search 260/330.5

[56] References Cited UNITED STATES PATENTS 3,413,308 11/1968 Bockstahler 260/330.5

Primary Examiner-Howard T. Mars Assistant ExaminerA. Siegel Attorney, Agent, or FirmAlbert l-l. Graddis; Frank S. Chow; George M. Yahwak {57] ABSTRACT The present invention relates to novel benzo(b)thi0- phene derivatives of the general formula:

wherein Y represents a hydrogen or halogen atom; A represents a hydrogen atom or a phenyl group which may be substituted with a halogen atom or a lower alkoxy group; B represents a radical of the formula OR or NR R wherein R is an alkyl radical of l to 5 carbons which may be substituted with hydroxy, lower alkoxy, phenyl or phenoxy groups or a cycloalkyl or phenyl group which may be substituted by lower alkoxy or halogen atoms; R and Rflwhich may be identical or different, represent, if identical, hydrogen, alkyl radicals of 1 to 5 carbon atoms which may be substituted by hydroxy, lower alkoxy, phenoxy, di-lower alkylamino, or phenyl groups; or, if R is hydrogen, R represents either a hydroxyl or an amino group which may be substituted by lower alkyl, dialkyl, alkylidene, phenyl or acyl groups or a lower alkyl group which may be substituted by hydroxy, lower alkoxy, phenoxy, dialkylainino, pyrrolidino, piperidino or morpholino groups; R further is a cycloalkyl or phenyl group, which may be substituted by a halogen or a lower alkoxy radical; or R and R together with the nitrogen altom to which they are attached, may form an aziridine, pyrrolidine, piperidine, morpholine or piperazine ring which may be substituted by lower alkyl, hydroxyalkyli phenylalkyl, phenyl or acetyl groups; or A and B together with the C=N group may form a 5, 6, or 7-membered heterocyclic ring.

The present invention further relates to the processes for the preparation of these derivatives and to the salts of these compounds with physiologically acceptable inorganic alid organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, fumaric acid, oxalic acid, citric acid, etc., and the quaternary ammonium compounds.

16 Claims, No Drawings NOVEL BENZO(B)THIOPI-IENE DERIVATIVES AND PROCESSES FOR THEIR PREPARATION Among the known analgesic, antipyretic, and antiinflammatory preparations in wide use today are phen- COOR' lll SH llla In the above procedure a thiosalicylic acid ofthe general formula II, in which R represents hydrogen or a lower alkyl group, and Y represents a halogen or hydrogen, is transformed into the corresponding benzo(b)thiophene isomeric derivatives of formula I by reaction with the imidates or amidines of the general formula II], or with the salts thereof as shown by the general formula Illa. ln formulas I, III and llla, A represents a hydrogen atom or a phenyl group which may be substituted with a halogen atom or a lower alkoxy group; B represents a radical of the formula OR or NRR, wherein R is an alkyl radical of l to carbons which may be substituted with hydroxy, lower alkoxy, phenyl or phenoxy groups or a cycloalkyl or phenyl group, which may be substituted by lower alkoxy or halogen atoms; R and R, which may be identical or different, represent, if identical, hydrogen, alkyl radicals of l to 5 carbon atoms which may be substituted by hydroxy, lower alkoxy, phenoxy, diloweralkylamino, or phenyl groups; or, if R is hydrogen, R represents either a hydroxyl or an amino group which may be substituted by lower alkyl, dialkyl, alkylidene, phenyl or acyl groups or a lower alkyl group which may be substi tutea by hydroxy, lower alkoxy, phenoxy, dialkylamino, pyrrolidino, piperidino, or morpholino groups; R further is a cycloalkyl or phenyl group which may be substituted by a halogen or a lower alkoxy radical; or R and R" together with the nitrogen atom to which they are attached may form an aziridine, pyrrolidine, piperidine, morpholine or piperazine ring which may be substituted by lower alkyl, hydroxyalkyl, phenylalkyl, phenyl or acetyl groups; and A and B together with the C=N group may form a 5, 6, or 7-membered heterocyclic ring. X represents the anion of an inorganic or organic acid.

In a preferred group of compounds according to formula l, Y is hydrogen or chloro; A is hydrogen, phenyl, methoxyphenyl, chlorophenyl; B is a radical of the formula OR or NR R wherein R is an alkyl radical of l to 5 carbon atoms which may be substituted by hydroxy, lower alkoxy or phenoxy groups or a cyclohexyl, phenyl, methoxyphenyl or chlorophenyl radical; R and R, which may be identical or different, represent, if identical, hydrogen, alkyl radicals of l, to 5 carbon atoms which may be substituted by hydroxy, lower alkoxy, phenoxy, dilower=alkylamino, or phenyl groups; or, if R is hydrogen, R represents either a hydroxyl or an amino group which may be substituted by lower alkyl, diloweralkyl, alkylidene, phenyl, formyl, lower alkanoyl, benzoyl, pyridyl-carbonyL lower alkoxycrbonyl or a lower alkyl group which may be substituted by hydroxy, lower alkoxy, phenoxy, diloweralkylamino, pyrrolidino, piperidino, or morpholino groups; R further represents cycloalkyl of 5 to 7 carbon atoms or a phenyl group which may be substituted by chloro or a lower alkoxy radical; or R and R together with the nitrogen atom to which they are attached form an aziridine, pyrrolidine, piperidine, morpholine or piperazine ring which may be substituted by lower alkyl, hydroxyloweralkyl, phenylloweralkyl, phenyl of acetyl groups; or A and B together with the Cfl group may form a 5, 6 or 7-membered N-heterocyclic ring.

ln the group of the most preferred compounds according to formula I, Y and A are both hydrogen atoms, R is a lower alkylor alkoxy-alkyl group containing up to 5 carbon atoms, R is hydrogen and R is a dialkylaminoalkyl group containing up to 7 carbon atoms, an alkoxyalkyl group containing up to 6 carbon atoms or a pyrrolidinoethyl, piperidinoethyl, or morpholinoethyl group.

The reaction is carried out in the presence of either an alkali metal, alkali metal hydride, alkoxide, hydroxide, or carbonate, and a suitable solvent. Among the solvents that have been found to be suitable are water, lower alcohols, benzene, toluene, xylene, dioxane, tetrahydrofurane, and dimethylsulfoxide.

The reaction is further carried out at temperatures of 20l50C, preferably at 6080C, with the reaction times being between 30 minutes and several hours in bl A solution of 0.46 g ('0l02 mol) of sodium inl50 ml. length. 1 of methanol is 'mixed. with =1 5 g'(0.2 mol) of chlo- Following this procedure, it is not necessary to use roacetonitrile and stirred at room temperature for l the imidates or amidines of formula III in substance; the h r. This m Xlre i added dropwise to a solution of solutions employed for the preparation of the specific 5 33.6 g (0.2: of methyl thiosalic-ylate and 112 g imidates or amidines may be us d dir tl l (0.2 mol) of potassium hydroxide in 200 ml of water.

The compounds prepared according to this proce- The mixture thus obtained is heated under reflux for dure may be further transformed into h i l i all 2 hours, diluted with water, and the precipitate is reacceptable salts following recognized pharmaceutical crystallized y acetate/acetone Solutionm l 10 c. A solution of 23 g (1 mol) of sodium in l l of anhy- A di a Second procedure; drous methanol is mixed with 84 g (0.5 mol) of lzl IV ILR2R3 t lb compounds of the general formula lb can also be ()bmethyl thiosalicylate while stirring. Tl'llS iS then tained by reacting compounds of the general formula mixed With 79 g of ethyl chl ro- Ia with amines of the general formula lV without a sola midate hydrochloride and heated under reflux vent or in a suitable solvent such as water, a lower alco- 10 llOllrS- he dium chloride precipitate is filhol, dimethylformamide, or dimethylsulfoxide, or in an lefed Off a the d sired product isolated by evapoexcess of amine of the formula [V at temperatures from 25 Fallon (y 73 g -P- 201 0 to 150 C, preferably at 2070C. A, Y, R, R and 3 have the meanings given in the fi t procedure The compound obtained in either of the three protoabove cols above is, based upon the melting point of 201C,

The compounds prepared according to this proceof the Same P ydure may be further transformed into physiologically EXAMPLE 2 acceptable salts following recognized pharmaceutlcal pmmcok Ethyl 3-hydroxy-benzo[b]thlophene-2-carboximidate According to a third procedure: v a. This compound is prepared as described in Example OH @U Y S\C%N A +R OH Y m N A I l. i fi 9" la compounds of the formula In or la may reciprocally be .1 (a) using ethanol instead of methanol. Yield is 30 converted into each other by transesterification with g of yellow crystals with an m.p..of. 194C. alcohols of the formula R" OH or ROH with an exb. The reaction described in Example 1 (c) is repeated change between R and R" taking place and R" using-anhydrous ethanol instead of methanol to obhaving the meaning stated for R. Y, A, and R have the min the compound stated. above. mea i g giv n above. c. 33.6 g of methyl thiosalicylate are dissolved in 400 The properties of the new compounds and their ml Of anhydrous dioxane. Adding 9.6 g Of sodium hymethods of preparation under the three procedures dride ina per cent oil suspension yield the sodium outlined above are demonstrated by the following ex- Salt, Precipitated 353 Yellow, voluminous P p amples which are to illustrate, but not limit the present A Solution of -3 g of ethyl chloroacetimidate in 200 invention ml of anhydrous dioxane is added dropwise to this suspension while stirring, and the mixture is heated to. 70 for 2 hours. It is then poured into water and the EXAMPLE 1 .product isolated by filtration.

Methyl A l The compound obtained in either of the three proto- 3-hydroxy-benzolb]thlophene-2-carboximidate I cols above is, based upon the melting point of 194C, a. A solution of 0.46 g 0.02 mol) of sodium in 150 ml ofthe 'p yof methanol is mixed with 15.1 g (0.2 mol) of chloroacetonitrile and stirred at room temperature for 1 hour. This mixture is added dropwise to a solution of EXAMPLE 3 33.6 g (0.2 mol)'of methyl thiosalicylate'and 4.6 g. 1 (0.2 mol) of sodium in 200 ml of methanol. The mixpropyl F W ture thus obtained is heated under reflux for 30 min- 16.8 g (0.1 mol) of methyl .thiosalicylate are added utes, poured into water, and the precipitate filtered dropwise to a'solution of 4.6 g (0.2 mol) of sodium in off. Recrystallization from ethyl acetate/acetone so- 400 ml oftanhydrousn-propanol. To this mixture 17.2

lution yields 30.2 g of yellow crystals with an m'.p. of g (0.1 mol) of propyl chloroacetimidate hydrochloride 201C. 1 are slowly added and the resultant mixture is heated under reflux for 6 hours. The reaction mixture is evapo-.

rated under vacuum and the residue distributed be tween water and dichloromethane. The organic phase is dried, evaporated, and the residue recrystallized from ethyl acetate/diisopropylether solution to yield 6.2 g of yellow crystals with an m.p. of 185C.

being formed is constantly distilled off by passing. through a stream of nitrogen. Evaporation to dryness and recrystallization of the residue from ethyl acetate yields yellow crystals with an m.p. of 208C.

EXAMPLE n-Butyl 3-hydroxy-benzo[b]thiophene-2-carboximidate TABLE l Ex. R m.p.(C) solvent 6 C H 198 ethyl-methylketone CH CH 7 CH 200 ethyl acetate CH 8 CH- -CH 211-212 ethyl acetate 1, 9 CH.,---C(CH;,) 2l l2l2 ethyl acetate 10 CH -CH -OCH l43-l44 ethyl acetate] petroleum ether 11 CH CH,-OC,H l 14-l l6 ethyl acetate/ petroleum ether 12 CH- -CH-;OC H 169-l7l ethyl acetate] petroleum ether 15 CH CH- -OH 169 acetone 16 CH CH -CH OH 178 acetone/dioxane EXAMPLE 1? 2-amidino-3-hydroxy-benzo[ b]thiophene tion a. To a solution of 8.7 g (0.38 mol) of sodium in 350 I b. 3 g of methyl 3-hydroxy-benzo[b]thiophene-2 carboximidate (Example 1) in ml of concentrated aqueous ammonia solution and 10 ml of methanol are stirred at room temperature for 20 hours.

The precipitate is filtered and recrystallized from ethyl acetate/isopropanol solvent solution yielding 2.5 g of yellow crystals.

0. 3 g ofmethyl 3-hydroxy-benzo[b]thiophene-2- c arboximidate (Example 1) are dissolved in 100 ml of methanol and heated under reflux for 10 hours while bubbling a stream of ammonia through the mix- '4 ture. Theresidue obtained after evaporation of the solvent is recrystallized from ethyl acetate/isopropanol solvent solution yielding 2.5 g of yellow crystals.

The compound obtained in either of the protocols above is, based upon the melting point of 249C, of the same purity.

EXAMPLE 1s 2-( N-ethyl-amidino)-3-hydroxy-benzo[b]thiophene a. To a solution of 6.4 g (0.28 mol) of sodium in 400 mlof methanol first 23.6 -g (0.14 mol) of methyl thiosalicylat'e, then 22 g (0.14 mol) of N-ethyl-2- chloroacetatnidine-hydroehloride are added and the mixture is heated under reflux for 6 hours. Further processingisaccording to Example 17 a. Yield upon recrystallization from an ethyl acetate/isopropanol solution it's 43 g of yellow crystals having an m.p. of 196C.

3 g of ethyl 3-hydroxy-benzo[b]thiophene-2- earboximidat' (Example 2) are heated under reflux for 10 hours in 20 g of 33 percent aqueous ethylamine solution. The residue obtained after evaporais recrystallized from an ethyl acetate/isopropariol solution and yields 2 g of the product. t

The compounds obtained above are, based upon the melting point of 196C, of the same purity.

EXAMPLE 19 2-(N-aminoamidino )-3'hydroxy-benzo[ b]thiophene A solution of 21 g of methyl 3-hydroxybenzo[b]thiophene-3-earboximidate (Example 1) in 250 ml of methanol is mixed with 10 g of 100% hydrazine'hydrate and heated under reflux for 1.5 hours. Subsequently the mixture is cooled in an ice bath, the precipitate filtered and recrystallized from diethyleneglycol monoethyl ether solution to yield 19.4 g of ye]- low crystals having an m.p. of 242C (decomp.).

The compounds listed in Table ll can be prepared in the same manner as described in Examples 17-19. (In formula 1, A would represent hydrogen).

TABLE l1-C0ntinued Example 8 ln.p.(C) solvent on NH-NHC() 299-301 dimutllylt'ornlalnidc/ N wzllcr (ll NH--NH( 318-320 ethanol ()2 NHNH-COH Z2744 methanol (13 NH NH-CO- (H3 220 ethanol (14 NHNH-COC.;H,-, 304 methanol o5 NH NH -co-cc ,ll 331) etlmnol 66 M Call; 1;, 1X5 lSOPl'OPtlllOl EXAMPLE 67 EXAMPLE 71 2-(N.N'-diphenyl amidino)-3-hydroxybenzo[b]thiop-methoxy-phenyl phene 3hydroxy-benzo[b]thiophene-2-N-phenyl- A solution of 2.3 g (0.1 mol) of sodium in 150 m1 of carboxlmdate methanol is mixed with 16.8 g (0.1 mol) of methyl thi- A solution of 16.8 g (0 1 of methyl li yosalicylate and then a solution of 24.4 g (0.1 mol) of late in 100 ml of anhydrous dioxane is added dropwise N,N'-diphenyl-2'chloro-acetamidine in 250 ml of to a p n i of 4- g of sodium hy e methanol is added. After heating under reflux for 1 Oil suspension) in 300 ml of nhy dioxane hour, the mixture is r d i t i water d h while stirring. The sodium salt of the methyl thiosalicycipitate filtered and recrystallized from an ethanol/walate Separates as a y voluminous precipitate T0 ter solution to yield 26.5 g of yellow needles having an this Suspension is added dropwlse a Solution of g f 152 153 (0.1 mol) of p-methoxy-phenyl N-phenylchloroacetimidate in 80 ml of anhydrous dioxane, the EXAMPLE 68 mixture is then heated to 70C for 1 hour and evapo- 2-(N,N-bis-p-ethoxyphenyl-amidino)-3-hydroxy-ben 30 rated under reduced pressure. The residue is mixed zowlthiophene with water and extracted with dichloromethane. After evaporation of the dried organic phase a residue reg olfmethyl thwsah'cylate are reacted as f mains which is recrystallized from ethyl acetate/diiso- PIC 67 14 g of Sodlum 'bls(p propylether solution. Analysis of the product shows: ethoxy-phenyl)-2-chloro-acetamldlne-nltrate1n 300 ml Yield: 81 g of yellow crystals 145C of anhydrous ethanol. After recrystalllzatlon from methanol/water 12.3 g of yellow crystals are obtained EXAMPLE 72 which sinter to a glassy mass at a temperature of puchlormphenyl 87 9OC and melt at l Isa-122C 3-hydroxy-benzo[b]thiophene-2-N-phenyl- EXAMPLE 9 4O carboximidate 2 (N pheny| Nr diethyl amidino) 3 hydroxy Preparation follows the protocol of Example 7 1 using benzo[b]thiophene hydrochloride 28 g of p-chloro-phenyl N-phenyl-chloroacetlmldate instead of p-methoxy-phenyl N-phenylg of methyl thiosalicylate are reacted as m chloroacetimidate. Analysis of the product when crysample 67 with g of Sodium and g of tallized from an ethyl acetate/diisopropyl ether shows: diethyl-N'-phenyl-2-chloro-acetamidine-oxalate in 700 Yield. 54 g of yellow crystals with an mp of 1380C ml of anhydrous methanol. After the reaction is completed, the product is evaporated under reduced pres- EXAMPLE 73 sure and the residue distributed between water and di- Ethyl chloromethane. The organic phase is dried and evapo- 3 h d b [b] h1 h -2 N- h rated, and the oily residue dissolved in ethyl acetate carboximidate and .mmsformed into the .hydrofzhloride by h intro- Following the protocol of Example 67, 17 g of ethyl ductlon of hydrogen chlorlde. Yleld upon purlflcatlon from an ethanol/isopropanol solution is 10 g having an 5 Nipllenyl-chloroacetlmlclate and 15 methyl thl p of 232C osallcylate are reacted with 4 g of sodlum ln anhydrous ethanol. Crysta1llzatlon from ethanol ylelds 17 g of yel- EXAMPLE 70 low crystals with an m.p. of 808lC. Phenyl EXAMPLE 74 3-hydroxy-benzolb]thiophene-2-N-phenyl' Eth l carboximidate 5-chloro-3-hydroxy-benzo[b]thiophene-2- Following the protocol of Example 67, 9 g of yellow carboxlmldate needles are obtained from reacting 21.8 g of methyl thi- This compound is prepared as described in Example osalicylate, 6 g of sodium, and 32.1 g of phenyl N- 2a using methyl 5-chloro-thiosalicy1ate instead of phenyl-chloroacctimidate in 300 ml of methanol. These have an m.p. of l4614 7C and are recrystallized from an ethyl acetate/diisopropylether solution.

methyl thiosalicylate. Crystallization from acetone/ethanol solution yields yellow crystals with an m.p. of 236C.

EXAMPLE 75 the procedures of Example 2a yields the desired compound. Recrystallization from acetone/ethanol solution yields a product in the form of yellow crystals with an mp. of 226C.

EXAMPLE 76 2-( 2-imidazo1in-2'-yl)-3-hydroxy-benzo[b]thiophene a. To a solution of 2.3 g (0.1 mol) of sodium in 250 ml of anhydrous methanol are added 15.4 g (0.1 mol) of thiosalicylic acid, 15.5 g (0.1 mol) of 2- chloromethylimidazoline-hydrochloride, and the mixture is heated under reflux for 6 hours. After evaporation under reduced pressure, dissolution of the residue in methanol water solution, and mixing with ammonia, the yellow precipitate (6 g) is filtered off and recrystallized from n-propanol/dimethy1formamide solution to yield the product having an m.p. of 304C (decomp.).

1. 11.2 g of 2-(2-imidazolinyl-methyl-thio) benzoic acid hydrochloride, m.p. 175 (crystallized from isopropanol solution) areobtained by evaporating the aqueousalkaline filtrate, mixing the residue with concentrated hydrochloric acid, and filtering the colorless precipitate. Heating above the melting point causes cyclisation to the title compound with the splitting off of a water and hydrogen chloride molecules.

b. A solution of 15.5 g (0.075 mol) of methyl 3- hydroxy-benzo[b]thiophene-Z-carboximidate (Example 1) is slowly dropped into a boiling solution of 18 g (0.3 mol) of ethylene-diamine in ml of methanol. The mixture is kept boiling for 2 hours, then cooled in an ice bath and the precipitate filtered. Recrystallization from dimethylformamidelwater solution yields 7.4 g of yellow crystals with an m.p. of 304C.

The compounds listed in Table 111 can be produced in a similar manner to Example 76.

TABLE Ill-Continued EX. Z rn.p,C solvent N methyl-ethyl- 83 C 290 ketonc/dimcthylforniamidc N 84 C 240-2 acetone 85 C n 194-6 ethanol NCH 86 C l 216-7 acetone OCH The Benzo(b)thiophenes and their pharmaceutically usable salts prepared according to the invention exhibit novel and valuable pharmacological properties. They especially exhibit anti-inflammatory effects with a resultant low toxicity and with the absence of the typical ulcerating effect on the mucous membranes of the digestive tract as found resulting from many commercially available anti-inflammatory ingredients.

To show the utility and safety of the compoundsof the invention when used for their anti-inflammatory properties, the following series of tests were performed.

PHARMACOLOG'ICAL RESULTS The compound, ethyl-3-hydroxybenzo(b)thiophene-2-carboximidate (Example 2) is chosen as a typical representative of the group of benzo(b) thiophenes, although results on other compounds of this invention also appear. This substance has pharmacological properties similar to those known as active anti-inflammatory preparations with analgesic and antipyretic properties, such as phenylbutaz one (4-n-Butyl- 1,2-diphenyl-3,S-dioxo-pyrazolidine), azapropazone (3-Dimethylamino-7methyl-l ,2-(n-propy1malonyl)- 1 ,2-dihydro-l ,2 -benzotriazine-dihydrate),acetylsalicylic acid (Aspirin), and indomethacin (l-(p- Chlorobenzoyl)-5methoxy-Z-methylindole3-acetic acid).

In order to show the superiority of these novel compounds over that of the known anti-inflammatory preparation, the following pharmacological tests were carried out on both the novel compounds and the four known preparations above. A comparison of the results obtained shows the superiority of the compounds according to this invention.

A. ACUTE TOXICITY Experimentalanimals are male mice (NMRUweighing 16 to 24 g and male rates (SIV 50) weighing to g. I

Prior to the beginning of the test, all animals are kept fasting for 16 mi 8 hours, however water is offered ad libitum. 6 mice and 4 or 6 rats belonged to each dosage group and the doses between each group are increased logarithmically. The volume of liquid administered during testing amounted to 2 ml/lOO g body weight. The substances tested are suspended in 1 percent Tragacanth mucilage and administered intragastrically via a gastric tube.

The results based upon the LDO for the compounds tested are tabulated below.

Acute Toxicity in Mice and Rats Animal Substance Route of LD,, 0 Confidence Limits Adminismg/kg in mg/kg tration p 0.05

lower upper Mouse Example 2 i.g, 3.890 3.268 4.629 Mouse lndomethacin Lg 10 Mouse Azapropazone Lg, ca.3000

5.000 Mouse Phenylbutazone Lg, 714 517.3 985.3 Mouse Acetylsalicylic Lg. 1.878 1.433 2.460

Acid Rat Example 2 Lg. 4000 Rat Indomethacin Lg. 30 Rat Azapropazone Lg. ca.3.000

6.000. Rat Phenylhutazone Lg 598 524.5 681.7 Rat Acetylsalicylic i.g. 2.065 1.298 3.285

Acid

B. YEAST EDEMA AND DETERMINATION OF PAIN THRESHOLD Test animals are male rats (SIV 501 weighing 100 to 180 g. All animals are kept fasting for 16 to 18 hours prior to the beginning of the test, however, water is offered ad libitum. 10 animals belonged to each dosage group. The volume of liquid administered during testing amounted to 2 ml/lOO g body weight. The substances tested are suspended in 1 percent Tragacanth mucilage and administered intragastrically via a gastric tube.

The volume of the paw is determined according to the method described by Enders and Heidbrink, the pain threshold according to that described by Randall and Selitto (Arch. Int. Pharmacodyn CXI: 409, 1957).

Following initial measurements, 0.05 mole ofa 5 percent suspension of dried yeast is injected subplantarly into the right paw and the test substances are administered immediately. The blank control group is given Tragacanth mucilage only. After 3 hours the pain threshold and the volume of the paw are determined again.

The mean value of the increase in paw volume of the animals of the blank control after 3 hours is rated 100 percent, and the mean value of the increase in paw volume of the animals of the substance groups expressed as a percentage thereof. Pain threshold after 3 hours reflects the increase or decrease in percent, compared to the initial value.

In order to be able to calculate the ED according to the method by Lichtfield and Wilcoxon (J.P.E.T. 96:99, 1949), those animals in a dose group are considered protected when the paw swelling was at least 40 percent less than that of the blank control.

The results based upon both increase in paw volume and pain threshold for the materials tested are tabulated below.

Influenceof the Example 2 compound, Indomethacin, Phenylbutazone, Azapropazone. and Acetylsalicylic Acid on the Yeast Edema of the Rat Paw C. CARRAGEENIN EDEMA Test animals used are the same as stated under Example B and up to the initial measurement, the procedure corresponded to that described under this example.

After an initial measurement, the test substances are administered and after 60 minutes a 1 percent Carrageenin suspension is injected subplantarly (0.1 ml/paw). After 60 and minutes the paw volume is again determined. Here, too, the blank control group was treatedwith the carrier alone.

The increase in the volume of the paw after 60 minutes is considered as the first phase of the biphase edema and thatafter 180 minutes, as compared to the 60-minute-value, as the second phase. Moreover, the total increase of the paw edema within 180 minutes, as compared tothe initial value, is also determined.

Determination of the influence exerted by the substances uponthe development of the paw edema and calculation of the ED are done as under Example B.

The results showing the effects of the materials tested upon the biphase edema are tabulated below:

Influence of the Example 2 compound, lndomethacin, Phenylbutazone, Azapropazone, and Acetylsalicylic Acid onthe Carrageenin Edema of the Rat Paw D. KAOLIN EDEMA Test animals used are the same as stated under Example B and up to the beginning of the test, the procedure corresponded to that described under this example.

After an initial measurement, a sterile 25 percent kaolin suspension was injected (0.05 ml/paw) subplantarly. The test substances are administered immediately, and after60, Y120, and 180 minutes the paw volume is again determined. 1

Evaluation of the tests were performed as stated under Example C, and the results soobtained pres- 5 ented below:

Influence of the Example 2 compound, Indomethacin. Phenylbutazone, Azapropazone, and Acetylsalicylic Acid on the Kaolin Edema of the Rat Paw Substance Dose 60 Mins. I20 Mins. I80 Mins.

mg/kg 7: 7r "7! Tragacanth I I00 100 Example 2 25.0 36 44 50 Example 2 50.0 62 40 d 5 Indomethacin 2.5 79 8i 8] Phenylbutazone 90.0 I07 I00 8 I Azapropazone 250.0 I00 93 67 Acetylsalicylic 300.0 156 93 82 Acid IE. :COTT'ON-PELLET TEST .Test animals are male rats (SIV 50) weighing 110 to 200 g. All test animals are kept fasting for 16 to 18 hours prior to the implantation of the pellets; after that food and water were available ad libitum. Each dose level ofthechemical tested was administered to 12 ani- 'mals. The-substances were suspended in 1% Tragacanthmucilageand administered intragastrically by means of a stomachtube. The substances to be investigated and the control suspensions are administered once on the operating day following operation, and

twice a day on the following 6- days (at intervals of 6 to 8'hours).The type of application and volume of liquid corresponded to that under B.

Under light ether anesthesia 4 sterile cotton pellets were implanted-under the skin on the back of the animal. The weight of one'pellet was 50 mg i 0.5- mg.

After-7 days treatment, the animals were sacrificed, the

pellets removed with the granulation tissue, weighed and then dried in the incubator at +80C'toconstant Influence oi the Example 2 compound, Indomethacin Phenylbutazone. Azapropazone, and Acetylsalicylic Acid on Development of the Granulation Tissue in r the Cotton-Pellet Test Substance Dose Granulation Tissue Increase in mg/kg (Dry Weight) Body Weight Tragacanth I00 normal Example 2 i 2 X 75 78 not influenced Indomethacin 2 X 1.5 80 not influenced Phenylbutazone 2 X 90 78 not influenced Azapropazone 2 X I50 76 not influenced ,Acetylsalicylic 2 X 200 I 89 not influenced Acid F. GRANULOMA POUCH TEST Test animals and the method of application of the dosages of the various test substances used are the same as under Example E.

Under light ether anesthesia 25 ml of air are injected under the shaved skin of the back. 0.5 ml of croton oillanimal (0.05 percent) are injected into the pouch formed by the air, and evenly distributed over the back by turning the animal.

On the third day croton oil (3 percent, 0.5 ml/animal) is again injected into this pouch. After being treated for 7 days the animals are sacrificed, the quantity of secretion in the granuloma pouch determined, the granuloma pouch removed, and the weight of the dry tissue is determined according to the process described under Example E.

The average dry weights of the granuloma pouches and thequantities of secretion of the groups subjected mined.

Influence of the'E xampIe 2 compound, Indomethacin,

Phcnylbutazone. and Acetylsalicylie Acid on the Grunuloma Pouch Weight and the Fluid of the Pouch Substance Dose Granuloma Pouch Secretion Increase in 1 mg/kg Dry Weight '71 Body Weight Tragaczmth -l0.0 I00 normal Example 2 2 X 125 70 59 not influenced Indomcthucin 2X L5 98 I34 not influenced" Phenylbut'azone 2 X 90 84 96 not influenced Acctylsalicylic 2 X I 88 121 not influenced Acid *Exitus of an animal weight. The average dry weight of the granulation tissue of the control group was rated 100 percent, and deviations of the mean weights of the group treated with the test substance determined as a percentage thereof.

The weight of the animals is measured daily throughout the tests, and the percental increase determined. At

the end of some tests, moreover, the suprarenal glands are removed and their weight determined.

The results obtained showing the deviationof the granulation tissue dry weight and changes in body weight are tabulated below.

G. ADJ UVANT ARTHRITIS Test animals used are the same as described under Example E; food and wateris 'given ad libitum.

Onthe first day of the test a 0.8percent suspension of .Mycobacteriumbutyri'umin paraffin (0.05 or 0.1 .ml/paw) is injected subplantarlyinto the left hind paw of the animals. After 18 days those animals in which the untreated hind'paw showed no clear arthritis are withdrawn from the test. From the 19th to the 22nd day the animals showing a reaction are treated intragastrically with the test substances. The right paw having been marked above the ankle-joint, the volume is determined daily from the 19th to the 22nd or 23rd day, according to the process described under Example B.

The volume of liquid, as well as of the carrier administered, corresponded to that described in the above tests.

The results based upon swelling of the animals paw is tabulated below.

surements are repeated over a period of 2 hours at intervals of 30 minutes. Each dose is administered to 10 animals selected from groups of animals following the initial measurements.

The test substances are administered as a suspension .in 1 percent Tragacanth mucilage, the volume of liquid amounting to 2 ml/lOO g of body weight.

The resultsare tabulated below.

Analgesic Activity of the Example 2 compound, lndomethucin.

Phenylbutazonc. Azapropazone. and Acetylsalicylic Acid in Mice during the Hot-Plate Test Substance ED; Confidence Limits Notes mg/kg in mg/kg p 0.05 lower upper Example 2 87.8 53.5 [43.9 lndomethacin slightly effective.

starting with mg/kg approx. 50% protection is achieved Phcnylbutazone .effect. but not dose dependent Azapropamnc ineffective Acetylsulicylic up to 400 nig/kg Acid ineffective l. ANTIPYRESIS Influence of the Example 2 compound, lndomethacin, Phenylbutazone, and Azapropazone on Arthritis Induced by Freund Ad-luvam Test animals are male rats (SlV 50) weighing 100 to subsmnce Doge swelling 180 g. 16 hours prior to the beginning of the test of 12 s r/r percent suspension of dried yeast (1 or 2 ml/100 g of body weight) is injected subcutaneously. When the Tragacanth 100 maximum of the increase in body temperature is Exampm 2 2 X 1250 81 reached followin 3 to 4 initial measurements the test lndomethucin 2 x 2.5 so t g Phenylbutazone 2 x 60.0 84 substances are applied intragastrically and the develop- Amfmpa'ne 2 X 250-0 ment of the body temperature is observed for a period H. HOTPLATE TEST of 7 hours.

The test substances administered are suspended in Tragacanth muscilage; the volume of liquid administered amounting to 2 ml/ g of body weight. In this test 2 control groups are used, one given sodium chloride subcutaneously (normal temperature group) and to the other group a yeast suspension is administered subcutaneously but, instead of the test substances, Tragacanth mucilage is administered intragastrically (fever control group).

The influence of the Example 2 compound and of the control substances on the increased body temperature of the rat are shown in the following graphs, which clearly show the superiority of the Example 2 substance for decreasing body temperature.

J. Summary Of Pharmacological Results For Ethyl-3-Hydroxy-Benzo( b) Thiophene-Z-Carboximidate (EXAMPLE 2) Calculating the ED on the basis of the results obtained from Examples A, B, and D, the following values The methods applied for investigating these substances corresponded to those described underthe above examples. In the hot ,plate test, however, the ED was not determined, but prolongation of the reaction time following-administration of the substance was are obtained.

Substance ED not shown-directly. In the temperature test no graph' mglkg 27 was made of the results; the table showing the decrease p 3 of normal body temperature following administration lower upper of the substance. Exam 1e 2 93 I 65 l 133 I The results obtained from the various pharmacologlndorrl ethacin 0:9 0:31 2:54 lea] test.sare tabulated below: Phenylbutazone 20.1 13.0 30.9 u Azapropazone l 17.0 73.5 186.0 Acetylsalicylic 192.0 153.6 240.0 f Acute bxicn 11. Mice ACld Substance Route of adnlinistratio'n LD 50 mg/kg Example 1 0 ig. 1.600 From the ED and LD (A) the following therapeu- Example 30 1 approx. 1.000 tic ratios for this test are callculated: l' 30 L000 Exarnple 31 1g. 1.600 Example 31 sc. 800 5 Example 33. sc. approx. 1.000 Example 2 42,9 Example 34 sc. approx 600 l d Example 10 ig. approx. 1.600 ethacin 33.3 E l H 1 600 Ph 1b t 29.7 Xampe g igi il gg Example 41 ig. approx. 1.600 Acetylsalicylic Acid 10.7

According to this calculation,.the therapeutic ratio f E h 3 h d b (b) hi h 2 Yeast Edema And lDottierrrkiil'ltaiiion of Pain Threshold n e a aw carbox1m1date is very good. It is not possible to calcu- Substance Route f udmidose vohmc pain late a therapeutic ratio for Azapropazone, since, be- I msll'fllwn s hold cause of the evidently irregular absorption of the subi m0 23 stance, no exact LD is obtained. Example 1 ig. 7s 32 10 As shown 7 in 11 only the Ethyl-3-hydroxyggfj 30 :2; g g3 33 benzo(b)thiophene-Z-carboximidate showed sufficient tragacalnth ig. I 100 39 analgesic activity in this experimental setup. 1n the case e I g: Y 2 ,3 of the standard substances, the analgesic activities were Exarnple 33 sc. 225 46 34 I NaCl 'sc. 100 10 not pronounced enough or there were not such act1V,,l Example 34 so 25 54 7 t1es so that it was not poss1ble to calculate an ED tragacanlh ig. 100 9 While commercially available anti-inflammatory 52212 23 1:- E 3 preparations exhibit an effect in some test models and Example 10 '1 ig. 200 73 49 tragacanth I ig. 100 35 are even meffective in others, the ant1 inflammatory Bump? l0 ia. 250 33 effect of the Example 2 compound 1s proved 1n all test trag'acanth. ig.. 100 Y 15 Example 11 I ig. 200 41 +32 models. The strength of the effects achieved is of the indomethucin vig' 5 100 same order as that of the most potent commerclally i 1 available anti-inflammatory preparations. Compared to customary anti-inflammatory preparations, the analgesic activity ofthe Example 2 compound is particularly marked. The antipyretic effect is also seen to be stronger than that of comparable substances. H

Doses as Iow as 5 mg/kg have a clear anti I lnflucncepn'fcarrageenin Edema OfThe Rat Paw Substance Rout'bf admini- :dose 1st phase 2nd phase 3 hrs.

inflammatory effect. In the hot plate test, 87.8 mg/kg titration 4 0, extends the reaction time of 50 percent of the animals i g/kg by 100 percent. In the antipyresis test, 150 mg/kg was tragacamh 100 considerably more-effective than 30 Q mg/kg of acetyl- 211C! I l 100 12 3 1 xamp e. m" N salicylic ac1d. a Example-30 sc.' 150 39 68 51 Compared with toxicity levels 'of the standard subp 31 Sci I 58 2 37 Example 33 sc. 150 59 17 39 stances used 1n the testmg, those of the Example 2 com- Bump: 34 00 47 44 44 pound are very favorable. Owing to the low doses re- Example 10 250 79 36 53 65 Example 11 1g. 250 62 43 54 qu1red for achlevmg antl-lnflammatory, analgesic, and Example 41 ig 78 28 51 antipyretic effects, an extraordinarily favorable therap pg 400 79 21 55 azone peutic ratio is also obtained.

Substance Route of admioidose 60 min. 120 min. I80 min.

.xtt'ation tog/kg 'J i; '2}

tragacanth ig. I I00 I00 Example l0 ig. 200 07 47 46 Example ll ig. 50 40 3h 56 Example ll ig. I00 22 27 46 acetylsaliig. 300 I56 93 R2 cylic acid Influence ()n The Development of Granulation Tissue In The Cotton Pellet Test Substance Route of adminidose granulation increase in stration tog/kg tissue Z body weight daily dry weight '7:

NaCl sc. 7 I00 27 indometacin ig. 2 l .5 9| l7 Example 30 sc. 2x501) X2 27 Example 30 .\'c. 2x751! (ill 27 tragacanth ig. I00 36 indomethaein ig. Ex I .5 65 28 Example 4! ig. 2x150 90 29 Influence Of Example 34 On The Granuloma Pouch Weight And The Granuloma Pouch Liquid Substance Route of adminidose granuloma sccreincrease stration mg/kg pouch dry lion in body daily weight I4 94 weight 1 tragacanth ig. I00 I00 55 Example 34 v ig. 2X50,0 79 75 5| phenylbuta ig. 2 90.0 l 84 96 57 zone Analgesic Effect Of The Substances In The Hot-Plate Test With Mice Substance Route of adminidose influence on the reaction time stration mg/kg in W tragacanth ig. +l 5 H 8 +26 Example I ig. 75.0 H43 H27 +48 +48 NaCl sc. +l 6 +20 +2 Example se. 125.0 +148 +140 +46 1 +3l NaCl sc. +l 2 +22 +27 Example 3| xe. [50.0 +5l +45 +29 +18 NaCl se. -2 y 2 8 8 Example 33 Se. 200.0 +306 +274 +244 +158 NaCl sc. 2 2 -8 -8 Example 34 sc. l00 0 +266 +202 +l26 +l00 tragacanth ig. +7 +17 +29 +48 Example l0 ig. 250.0 +83 +77 +98 +67 tragacantlt ig. t +22 +43 +37 +30 lixample l I ig. 200.0 +I03 +102 +l24 +l00 tragacanth ig. +9 +40 +49 +5l Example I l ig. 250.0 +l24 +l54 +144 +158 tragacanth ig. H5 H2 +l7 +l2 Example 4| ig. 200.0 +200 +250 +200 +l56 tragaeanth ig. +l6 +22 +l0 +20 azapropazone ig. 500.0 +l l +5 +15 +l l Influence On The Normal Body Temperature 0! The Rat 27 .2 Having thus described our invention and theiman ner hyd -b n Lb]thigphefie-Z-carboximidate. and process of making and using it, in such full, clear, 8. Novel benzo (b) thiophenes of the formula: OH ;1

. 4 NH c a concise, and exact terms as to enable any person skilled" i whereiniR is a radical selected from the group consistin the art to which it pertains, or with which it is most ing of:' clearly connected, to make and use the same, CH,CH

We claim: 1. Novel benzo[b]thiophenes of the formula:

ci-i wherein Y IS a hydrogen, or halogen atom; wherein A -CH CH (CH,)

is a hydrogen atom, a phenyl group substituted with a (CH3):-

halogen atom, or a phenyl group substituted with a lower alkoxy group; wherein B is a radical of the formula OR wherein R is an alkyl radical of l to 5 carbons.

2. The compound of claim lwhe'rein Y is a hydrogen atom, andwherein A is a hydrogen atom. I, v g

3. The compound of claim 2 which is Methyl-3- hydroxy-benzolblthiophene-2-carboximidate. compound of claim 8 wherein R is The compound ofwclaim 2 which is y 1l.Th e"c-ompound ofclaim8whereinRis CH C hydroxy-benzo[b1thiophene-Z-carboximidate. I c f The compound of claim 2 which is y I l2. The compound of claim 8 wherein R is CH- hydroxy-benzo[b]thiophene-2-carboximidate. 2 CH2' OCH3' l3'."The compound of claim 8 wherein R is CH- 6. The compound of claim 2 which is lsopropyl-3- CH CH hydroxybenzolb]thiophcne-2-carboximidate. compound f Ciaim 8 wherein R i C d f l 2 h' h -But l-3- 7 The compo O C mm n y 1s, The compound of claim 8 wherein R is -CH- }CH .-'OH.

16. 2'-methoxy-ethyl 3-hydroxy-benzolb1thiophenecarboximidate. 

1. NOVEL BENZO(B)THIOPHENES OF THE FORMULA:
 2. The compound of claim 1 wherein Y is a hydrogen atom, and wherein A is a hydrogen atom.
 3. The compound of claim 2 which is Methyl-3-hydroxy-benzo(b)thiophene-2-carboximidate.
 4. The compound of claim 2 which is Ethyl-3-hydroxy-benzo(b)thiophene-2-carboximidate.
 5. The compound of claim 2 which is Propyl-3-hydroxy-benzo(b)thiophene-2-carboximidate.
 6. The compound of claim 2 which is Isopropyl-3-hydroxybenzo(b)thiophene-2-carboximidate.
 7. The compound of claim 2 which is n-Butyl-3-hydroxy-benzo(b)thiophene-2-carboximidate.
 8. Novel benzo (b) thiophenes of the formula:
 9. The compound of claim 8 wherein R is
 10. The compound of claim 8 wherein R is -CH2-CH (CH3)2.
 11. The compound of claim 8 wherein R is -CH2-C (CH3)3.
 12. The compound of claim 8 wherein R is -CH2-CH2-OCH3.
 13. The compound of claim 8 wherein R is -CH2-CH2-OCH2-CH3.
 14. The compound of claim 8 wherein R is -CH2-CH2-OH.
 15. The compound of claim 8 wherein R is -CH2-CH2-OH.
 16. 2''-methoxy-ethyl 3-hydroxy-benzo(b)thiophenecarboximidate. 